Kinases are enzymes which transfer (phosphorylates) a phosphate group from a molecule having a high energy phosphate bond such as ATP to a substrate or a target molecule. Among them, protein kinases which are enzymes capable of phosphorylating protein molecules function as regulatory factors in various signal transduction pathways or metabolic pathways in cells. Functional abnormality of kinases often causes diseases such as cancer, and it has been expected that an agent having a function to inhibit a specific kinase is developed and the developed agent is used for treatment or prevention of diseases.
A serine/threonine kinase Pim-1 is a serine/threonine kinase which was at first identified as a gene to be often activated by murine leukemia virus (MuLV) insertion in a T-cell lymphoma caused by the leukemia virus (Non-patent document 1). Further, it is reported that Pim-1 in cytoplasm functions as a factor for inhibiting apoptosis in various hematopoietic cells (Non-patent document 2).
It is known that Pim-1 is expressed not only in hematopoietic cells but also in the lymphatic system, prostate gland, testis, and oral epithelial cells. It is also known that the majority of the function of Pim-2 and Pim-3 which are serine/threonine kinases and have significant sequence homology to Pim-1 overlaps with that of Pim-1 (Non-patent document 3).
Further, it is known that Pim-3 is expressed in malignancies in the pancreatic and liver cells, but is not expressed in normal pancreatic tissues, and it is reported that Pim-3 functions as a factor for inhibiting apoptosis in human pancreatic cancer cells and of hepatocellular cancer cell lines (Non-patent documents 4 and 5).
Non-patent document 1: Cuypers, H. T., Selten, G., Quint, W., Zijlstra, M., Maandag, E. R., Boelens, W., van Wezenbeek, P., Melief, C., Berns, A. Murine leukemia virus-induced T-cell lymphomagenesis: integration of proviruses in a distinct chromosomal region. Cell, 37: 141-150, 1984
Non-patent document 2: Selten, G., Cuypers, H. T. & Berns, A. Proviral activation of the putative oncogene Pim-1 in MuLV induced T-cell lymphomas. EMBO J, 4: 1793-1798, 1985
Non-patent document 3: Malte Bachmann, Tarik Moroy, The serine/threonine kinase Pim-1, The International Journal of Biochemistry & Cell Biology 37 (2005) 726-730
Non-patent document 4: Chifumi Fujii, Yasunari Nakamoto, Peirong Lu, Koichi Tsuneyama, Boryana K. Popivanova, Shuichi Kaneko and Naofumi Mukaida, Aberrant expression of serine/threonine kinase Pim-3 in hepatocellular carcinoma development and its role in the proliferation of human hepatoma cell lines, Int. J. Cancer: 114, 209-218 (2005)
Non-patent document 5: Ying-Yi Li, Boryana K. Popivanova, Youichiro Nagai, Hiroshi Ishiokura, Chifumi Fujii, and Naofumi Mukaida, Pim-3, a Proto-Oncogene with Serine/Threonine Kinase Activity, Is Aberrantly Expressed in Human Pancreatic Cancer and Phosphorylates Bad to Block Bad-Mediated Apoptosis in Human Pancreatic Cancer Cell Line, Cancer Res 2006, 66: (13). Jul. 1, 2006; 6741-7